Low dose modafinil for enhancement of cognitive function

ABSTRACT

Modafinil is shown to be effective in improving or restoring cognitive function in the humans or other mammals when administered at doses that are substantially lower than optimal wakefulness-promoting doses. Daily dosages of less than 100 mg/day and more particularly from about 1 to about 75 mg/day are shown to be effective.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention is related to the field ofneuropharmacological agents, including agents that affect the cognitivefunctions, and more particularly to the improvement of cognitivefunction in a subject in which cognitive function has been diminished.

[0003] 2. Description of Related Art

[0004] Modafinil (C₁₅H₁₅NO₂S), 2-(benzhydrylsulfinyl) acetamide, or2-[(diphenylmethyl)sulfinyl] acetamide, is a synthetic acetamidederivative with wake-promoting activity, the structure of which has beendescribed in French Patent No. 78 05 510 and in U.S. Pat. No. 4,177,290,and which has been approved by the United States Food and DrugAdministration for use in the treatment of narcolepsy. Modafinil wastested in combination with various agents including apomorphine,amphetamine, reserpine, oxotremorine, hypnotics, yohimbine,5-hydroxytryptophan, monoamine oxidase inhibitor (I.M.A.O.), and inseveral behavioral conditions, as described in the cited patents. Amethod of preparation of a racemic mixture is described in the '290patent and a method of preparation of a levorotatory isomer is describedin U.S. Pat. No. 4,927,855 (both incorporated herein by reference). Thelevorotatory isomer is reported to be useful for treatment ofhypersonmia, depression, Alzheimer's disease and to have activitytowards the symptoms of dementia and loss of memory, especially in theelderly. However, these patents do not appear to describe any effect ofthe levorotatory isomer on a loss of cognitive function due toAlzheimer's Disease, nor do they appear to describe any effects of a lowdose modafinil as described herein below.

[0005] Modafinil has also been described as an agent with activity inthe central nervous system, and as a useful agent in the treatment ofParkinson's disease (U.S. Pat. No. 5,180,745); in the protection ofcerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in thetreatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776);and in the treatment of sleep apneas and disorders of central origin(U.S. Pat. No. 5,612,378). U.S. Pat. No. 5,618,845 describes modafinilpreparations of a defined particle size less than about 200 microns thatis more potent and safer than preparations containing a substantialproportion of larger particles.

[0006] Various pharmacological agents have been described for treatmentof cognitive dysfunction. U.S. Pat. No. 5,602,131 describes ebumaneanalogs, heterocyclic inducers of tyrosine hydroxylase (TH). TH is anenzyme that controls the synthesis of the transmitter in the centralcatecholaminergic and dopaminergic neurons, and because the speed ofsynthesis of this transmitter is associated with the appearance of tonicdysfunctions of the brain, these compounds are proposed as therapeuticagents in the treatment of disorders such as anxiety, psychoses,depression, memory disorders in the course of senescence and/ordegenerative diseases and in Parkinson's disease. Other pharmacologicalagents that have been suggested for treatment of cognitive dysfunctioninclude heterocyclic compounds such as 3,4-diphenyl chromans (U.S. Pat.No. 5,756,539), tacrine metabolites (U.S. Pat. No. 5,767,126), andaza-cyclic compounds (U.S. Pat. Nos. 5,773,452; 5,919,805; and RE35,822), all of which are incorporated herein by reference. Thecompounds described in these patents appear to have in common theability to directly or indirectly affect cholinergic neurotransmitters,or the postsynaptic muscarinic receptors for cholinergic neurons. Otherproposed therapies for loss of cognitive function include polyaminecompounds for protection of overstimulation of NMDA receptors (U.S. Pat.No. 5,886,051) and a lipid soluble preparation of thiamine to improveglucose metabolism in the brain (U.S. Pat. No. 5,885,608).

[0007] There is still a need, however, for an effective treatment forthe restoration of cognitive function that is non-toxic and effectivefor long-term administration in order to improve the quality of life,and productivity of humans and animals subject to cognitive dysfunctiondue to advanced age or disease.

SUMMARY OF THE INVENTION

[0008] The present disclosure provides novel compositions of modafiniland methods of using these compositions that are effective at improvingcognitive function in a subject in need thereof It has been surprisinglyfound that administration of modafinil at doses much lower than theapproved doses known to promote wakefulness improves cognitive functionin aged rats to levels comparable to young controls. It is a furthersurprising discovery that this effect is not seen at doses of 200 to 400mg/day, normally used to promote wakefulness, or to treat excessivedaytime sleepiness (EDS) associated with narcolepsy, for example. Asused herein, the term “improving cognitive function” would encompassactivating, increasing, stabilizing, maintaining, enhancing or restoringcognitive function in a subject.

[0009] The present invention may be described in certain embodiments asa composition comprising a modafinil compound for administration to amammal, said composition including from about 1 mg to about 75 mg of themodafinil compound. A modafinil compound as described herein may includea racemic compound, and may be in an acid form, such as a metabolic acidof modafinil or a benzhydrylsulfinylacetic acid, a sulfone form, ahydroxylated form, a conjugated form such as a modafinil compoundconjugated to a protein, a polysaccharide, a glucuronide or a sulfate,or a polymorphic form. In certain embodiments the composition willinclude from about 1 mg to about 75 mg, from about 5 to about 60 mg,from about 25 to about 40 mg, or even about 30 to 35 mg of the modafinilcompound, wherein in certain preferred embodiments the modafinilcompound is modafinil.

[0010] It is also preferred that the composition as described abovecontain a single daily dose for administration to a mammal, andincluding a mammal that has a loss of cognitive function. Preferredcompositions will take various forms, but the most preferred are oralpharmaceutical preparations, and more particularly tablets for oraladministration. Such a tablet will contain the active ingredient, amodafinil compound or modafinil, for example, and may also include anyor all of the following inert ingredients: lactose, corn starch,magnesium silicate, croscarmellose sodium, povidone, magnesium stearate,or talc.

[0011] The compositions, preparations and pharmaceutical preparationsdescribed herein may be formulated and/or adapted for administration toa variety of preferably mammalian subjects, including veterinarysubjects as well as human subjects. Certain preparations andformulations as described herein will be beneficial in the treatment ofloss of cognition in human Alzheimer's disease patients, Age-RelatedCognitive Decline patients, or animal or human patients suffering orsusceptible to a temporary or permanent loss of cognitive function, forexample, due to advanced age, trauma, stress, disease, schizophrenia, ortransient impairment due to chemical imbalance or toxicity, such asethanol toxicity.

[0012] As such, the present invention also provides a method ofpreparing a composition for improvement of cognitive function in asubject in need thereof, where the method includes combining from about1 to about 75 mg, about 5 to about 60 mg, about 15 to about 50 mg, about25 to about 40 mg, or even about 30 to 35 mg of modafinil with apharmaceutically acceptable carrier. The composition may be adapted asdescribed above, and preferably is prepared as an oral pharmaceuticalpreparation, or more particularly a tablet for oral administration asdescribed above.

[0013] Another preferred embodiment of the invention is a method ofimproving a cognitive function in an animal or human subject, where themethod includes administering to the subject an amount of modafinileffective to improve the cognitive function. As shown herein, aneffective amount of modafinil may be substantially lower than theoptimum dose effective to promote wakefulness in a subject, and ispreferably lower than 200 mg/day in an adult human. It is a surprisingaspect of the present invention that the optimal wakefulness promotingdoses are much less effective at improving cognitive function than arelower doses. An aspect of the invention is, therefore, a method fortreating impaired cognition in a mammal susceptible to the developmentof or suffering from cognition loss, the method including administeringto a mammal amounts of a modafinil compound effective to improvecognition in the animal, where the amounts of modafinil compound beingadministered periodically in unit doses are substantially lower thanoptimum wakefulness promoting dosages in the mammal. As describedelsewhere herein, the optimum wakefulness promoting dose for an adulthuman is about 200 mg/day. As such, preferred unit doses provide dailydoses of from about 1 mg to about 75 mg orally, or the oral dosenecessary to achieve a serum level of modafinil of from about 0.05 toabout 2 μg/ml.

[0014] It is also an aspect of the present invention that a modafinilcompound such as modafinil may be combined with other pharmaceuticalagents, and more particularly, with agents that are useful for thetreatment of impaired cognition associated with various disease statesincluding, for example, age, trauma, stress or transient impairment dueto chemical imbalance or toxicity, hypersomnia, depression, Alzheimer'sDisease, non-Alzheimer's dementias, including Lewy body dementia,vascular dementia and binswanger's dementia, and schizophrenia. Thepresent invention would encompass, therefore, combinations of modafinilor a modafinil compound with ebumane analogs, heterocyclic inducers oftyrosine hydroxylase, 3,4-diphenyl chromans, tacrine metabolites,aza-cyclic compounds, polyamine compounds, or thiamine;nonanticholinergic antidepressants such as benzodiazepines;phenothiazines aliphatic such as chlorpromazine; piperidines such asthioridazine; piperazines such as trifluoperazine, fluphenazine andperphenazine; dibenzoxazepines such as loxapine; dihydroindolones suchas molindone; thioxanthenes such as thiothixene; butyrophenones such ashaloperidol; diphenylbutyl-piperidines such as pimozide;dibenzodiazepine such as clozapine; benzisoxazole such as risperidone;thienobenzodiazepine such as olanzapine; dibenzothiazepine such asquetiapine; imidazolidinone such as sertindole andbenzisothiazolyl-piperazine such as ziprasidone.

[0015] It is an object of the present disclosure also, to provide in amethod for using a modafinil compound in mammals as a medicine, animprovement which includes administering modafinil in unit doses thatare (a) substantially lower than the optimal unit doses that areeffective to promote wakefulness in the mammal and (b) effective tostabilize or improve cognition in the mammal, and preferably where themammal is susceptible to the development of or is suffering fromcognition loss.

[0016] The present disclosure also provides a pharmaceutical compositionin unit dose form, for use in treating loss of cognition in a mammalsusceptible to the development of or suffering from cognition loss,which includes an amount of a modafinil compound such that one or moreunit doses thereof are effective to stabilize or improve cognition inthe mammal upon periodic administration and the unit doses beingadministered periodically are substantially lower than an optimum dosageeffective to promote wakefulness in the mammal. Such a pharmaceuticalcomposition would preferably include the modafinil compound contained ineach unit dose that provides a stable serum level of about 0.05 to about2 μg/ml or more preferably, from about 0.1 to about 1.5 μg/ml of themodafinil compound upon daily administration of one or more unit doses,and may include a tablet for oral administration.

[0017] The present disclosure also provides a therapeutic package fordispensing to, or for use in dispensing to, a mammal being treated forloss of cognition, the package including (1) one or more unit doses,each such unit dose containing an amount of a modafinil compound suchthat said one or more unit doses thereof are effective to stabilize orimprove cognition in said animal upon periodic administration and theunit doses being administered periodically are substantially lower thana minimal optimum dosage effective to promote wakefulness in saidmammal, and (2) a finished pharmaceutical container therefor, saidcontainer containing (a) said unit dose or unit doses and (b) labelingdirecting the use of said package in the treatment of said mammal. Inpreferred embodiments the unit dose is adapted for oral administration.

[0018] The present disclosure also includes, in certain embodiments, amethod of treating dementia, or even dementia due to Alzheimer's diseasein a human subject in need thereof, where the method includesadministering to the subject a composition including modafinil in adaily dose that is effective to substantially improve the dementia andis lower than the minimal optimum daily dose that is effective topromote wakefulness in the human subject. Such a dose would, in certainembodiments include an oral dosage of less than 200 mg and morepreferably from about 5 to about 75 mg.

[0019] The present discovery may be described in certain aspects,therefore, as a composition comprising a low dose of modafinil for usein improving cognitive function in a subject in need thereof, such as asubject that has an age-related loss of cognitive function. In certainembodiments, an effective dose is from about 5 to about 75 mg, fromabout 10 to about 60 mg, from about 15 to about 50 mg, or about 30 to 35mg. A composition as described herein may be an oral pharmaceuticalpreparation, or even a tablet for oral administration.

[0020] Also described herein are methods of preparing a composition forimprovement of cognitive function in a subject in need thereof includingcombining an effective low level dose of modafinil as described in thepreceding paragraph with a pharmaceutically acceptable carrier. As usedherein, “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

[0021] The compositions comprising modafinil as described herein may beorally administered with an inert diluent or an assimilable ediblecarrier, for example. The compositions may also be enclosed in hard orsoft shell gelatin capsule, compressed into tablets, or incorporateddirectly with the food of the diet. For oral therapeutic administration,modafinil may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,solutions, suspensions, syrups, wafers, dermal patches and the like,although sustained release formulations are the generally preferredmethod of administering modafinil. Such compositions and preparationsshould contain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of the unit.

[0022] The tablets, troches, pills, capsules and the like may alsocontain the following: a binder, as gum tragacanth, acacia, cornstarch,or gelatin; excipients, such as dicalcium phosphate; a disintegratingagent, such as corn starch, potato starch, alginic acid and the like; alubricant, such as magnesium stearate; and a sweetening agent, such assucrose, lactose or saccharin may be added or a flavoring agent, such aspeppermint, oil of wintergreen, or cherry flavoring, for example. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit. For instance, tablets, pills, or capsules may be coatedwith shellac, sugar or both. A syrup of elixir may contain the activecompounds sucrose as a sweetening agent methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compounds may be incorporated intosustained or variable release rate preparations and formulations.Variable release rate formulations are those in which the rate ofrelease of the active agent varies over the dissolution time of a singledose of the formulation.

[0023] In certain embodiments, the disclosed compositions may beformulated to be administered by use of a skin patch, or transdermaldelivery system. The administration of the modafinil compositionsdescribed herein transdermally may be accomplished by any of a number ofsystems known in the art. Examples of systems that may be adapted foruse with the compositions described herein include those systems oftransdermal administration described in U.S. Pat. No. 4,816,252; U.S.Pat. No. 5,122,382; U.S. Pat. No. 5,198,223; U.S. Pat. No. 5,023,084;U.S. Pat. No. 4,906,169; U.S. Pat. No. 5,145,682; U.S. Pat. No.4,624,665; U.S. Pat. No. 4,687,481; U.S. Pat. No. 4,834,978; and U.S.Pat. No. 4,810,499 (all incorporated herein by reference).

[0024] These methods typically include an adhesive matrix or drugreservoir system and may include a skin permeation enhancement agentsuch as ethanol, polyethylene glycol 200 dilaurate, isopropyl myristate,glycerol trioleate, linolenic acid saturated ethanol, glycerolmonooleate, glycerol monolaurate, n-decyl alcohol, capric acid, andcertain saturated and unsaturated fatty acids, and their esters,alcohols, monoglycerides, acetate, diethanolamides andN,N-dimethylamides (See for examples, U.S. Pat. No. 4,906,169).

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The following drawings form part of the present specification andare included to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

[0026]FIG. 1 is data from delayed alternation studies in rats, whereopen squares indicate the percent correct responses in young controls,open diamonds indicate percent correct responses in aged controls, andfilled triangles indicate aged rats administered modafinil at 30 mg/kg.

[0027]FIG. 2 is data from delayed alternation studies in rats, whereopen squares indicate the percent correct responses in young controls,open diamonds indicate percent correct responses in aged controls, andx's indicate aged rats administered modafinil at 100 mg/kg.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0028] The present invention arises from the discovery that modafinil,when administered at low doses, is able to restore cognitive function inaged rats to levels seen in young rats. As shown in studies describedherein, aged rats show clear deficits in cognitive ability when comparedto young, matched control rats in a delayed alternation task. Thisage-related loss of cognitive ability is also shown herein to bedistinguished from an impairment in short term memory. Anothersurprising discovery as disclosed herein is that the enhancement ofcognitive function in aged rats occurs at dosages of modafinil that arelower than those known to produce wakefulness, and that at the normalwake-promoting doses, the enhancement in cognitive function disappears.These data suggest that the cognitive activity of modafinil arises froma different mechanism or target site than the wakefulness promotingactivity.

[0029] Cognition is a general term understood in the art as the qualityof knowing, and includes perceiving, recognizing, conceiving, judging,sensing, reasoning, and imagining, (See Stedman's Medical Dictionary,25^(th) edition, Williams & Wilkins, Baltimore). Disorders of cognition,or cognitive dysfunction may be characterized as forgetfulness,confusion, memory loss, attentional deficits, affective or emotionaldisturbances, and deficits in learning, association, consolidation andrecognition, and would include the condition known as Age-RelatedCognitive Decline. As such, an improvement in cognitive function asdemonstrated in the studies described herein, is a novel use formodafinil containing compositions. In addition to novel methods of use,modafinil is shown herein to be effective at improving cognitivefunction at low doses with respect to those shown to be effective inwake-promoting activity. The present discovery, therefore, represents anew and surprising use for modafinil and also provides for compositionsthat include modafinil at lower dosages than the optimal effective dosesthat are commonly used for narcolepsy or hypersomnia, for example.

[0030] It has been previously shown that aged rats (>18 months) showclear deficits as compared with young rats in the acquisition of anoperant delayed alternation task. Delayed alternation tasks have beensuggested as a potentially useful tool in the study of age-relatedmemory deficits in rats (Porsolt et al., 1995, Drug Development Research35:214). This task requires the rat to learn to alternate its responsesbetween two levers in a standard Skinner Box in order to obtain a foodreward. After having previously acquired a single lever-pressingresponse, the animal is given a series of trials consisting of thepresentation, via retractable levers, of a left or right lever, followed5 seconds later by the presentation of the two levers. The animal mustlearn to press the lever opposite to that which was presented 5 secondspreviously (delayed alternation) to obtain food.

[0031] The delayed alternation procedure measures drug effects onresponse accuracy (percent correct responses), attention (simplereaction time in a one lever presentation and response omissions), andinformation processing (choice reaction time in the two leverpresentation). The response accuracy is calculated as the number ofreinforced, or correct responses (delayed alternations) expressed as apercent of the total number of responses emitted in a choice responsebetween two levers. This measure is an indication of the learningcapacities of the animal during acquisition. The simple reaction time isa measurement of the time elapsed between the presentation of a lever atthe beginning of a trial and the moment when the animal pressed it. Thetime is expressed as the mean for the total number of trials initiated.This value indicates the general attention capacity of the animal torespond to an unpredictable spatial stimulus. The choice reaction timeis the time elapsed between the presentation of the two levers and themoment when the animal pressed a lever. This data is presented as themean for the total number of trials completed. This measure indicatesthe information processing speed of the animal. Response failures arethe number of times an animal fails to respond to either the singlelever or to both levers. Aged animals show deficits on all parameters.Modafinil, administered at doses of 60 mg/kg or less restored cognitivefunction in the aged rats to the level of the young control rats.

[0032] In another study, aged rats were tested for performance of astabilized delayed alternation task at three retention delays. Afterstabilized performance in training sessions the rats were entered into adrug testing study with 15, 30 or 60 mg/ml of modafinil. A trial startedwith the presentation of a single lever (left or right). A response onthis lever resulted in the retraction of the lever from the chamber, thedelivery of a food pellet and started a retention delay (5, 10 or 20seconds). After the expiration of the delay, the 2 levers were insertedinto the chamber and the animal received a food pellet only if itpressed the lever not previously presented (delayed alternation).Incorrect responses (responses on the same lever) were not reinforced.The 3 delays were randomly presented and equally distributed throughoutthe session. Correct or incorrect responses were followed by retractionof the two levers. If, during a one-lever or two-lever presentation, theanimal did not press a lever within 20 seconds, the lever(s) werewithdrawn without food reward (response omission). The test resultsindicated the response accuracy of the animal after each retentiondelay, the simple reaction time in the one lever presentation, and thechoice reaction time in the two lever presentation. In these studies,aged rats showed a clear decrease in response accuracy as a function ofthe retention delay, and modafinil did not significantly affect thenumber of correct responses at any retention delay. Therefore, modafinilhad no effect on improving short term memory at these doses.

[0033] An aspect of the present invention is the surprising activity ofmodafinil at lower dosages than has been observed to have an effect onwakefulness or alertness. The dosage levels in rats in the studiesdescribed herein are reported in mg/kg administered by intraperitonealinjection (i.p.). As described in previous publications, the wakefulnesspromoting dose of modafinil in rats is highly significant at doses of100 to 300 mg/kg i.p. (Edgar and Seidel, The Journal of Pharmacology andExperimental Therapeutics, vol. 283, pp 757-769, 1997). Theextrapolation in adult humans is a wakefulness promoting dose of 200mg/day. A dose of 200 mg to an adult human would result in a serum levelof about 6.4 μg/ml. Therefore, the doses as described herein to improvecognitive function would be most effective when the concentration ofmodafinil in the blood is between about 0.05 and about 2 μg/ml. Aneffective dose, therefore, is a dose given as a single unit per day in asustained release formula or given periodically would be that dose thatmaintains a serum level of from about 0.05 to about 2 μg/ml.

[0034] Prior to any invention disclosed or claimed herein, modafinil wasknown in the art in the form of a therapeutic package, marketed underthe name Provigil®. Provigil® is a pharmaceutical product marketed byCephalon, Inc. of West Chester, Pa. Provigil® is supplied as tabletscontaining 100 mg or 200 mg modafinil. In commercial use,modafinil-containing therapeutic packages in the prior art were labeledand otherwise indicated for use in narcolepsy patients.

[0035] Accordingly, known in the prior art were therapeutic packagesproviding one or more unit doses of modafinil as an active ingredientthereof, supplied in a finished pharmaceutical container that containsaid unit doses, and further contained or comprised labeling directingthe use of said package in the treatment of a human disease or conditionas described above. In the provided literature accompanying apharmaceutical container are instructions that the daily dosage ofmodafinil is 200 mg/day given as a single dose in the morning.

[0036] In particular, the package insert approved by the FDA for theproduct Provigil®, marketed by Cephalon, Inc. indicates the availabilityof 100 and 200 mg modafinil tablets. For example, the package insertindicates the availability of 100 and 200 mg. modafinil tablets. Thepackage insert further describes the manner in whichmodafinil-containing therapeutic packages were supplied for commercialuse or sale. The package insert cited above provides an example of thecomplete approved labeling t0hat comprised a part of the knowntherapeutic packages indicated for narcolepsy. The complete material mayalso be found, at the time of filing of the present application, on theWorld Wide Web at http://www.provigil.com.

[0037] The following examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLE 1

[0038] Modafinil was evaluated after i.p. administration in aged maleWistar rats, 23 months old, to evaluate its effects on the acquisitionof an operant delayed alternation task for food reward. After 3 weeks oflever-pressing training (single lever), each animal was submitted to adaily delayed alternation acquisition session (two levers) in a Skinnerbox for 2 consecutive weeks (10 sessions). In the delayed alternationacquisition sessions the animals were given 35 trials, each consistingof the presentation of one lever followed 5 seconds later by thepresentation of the two levers. The animals had to respond on the levernot previously presented (delayed presentation). Five measures weretaken: percent correct responses (response accuracy), simple and choicereaction times and the number of failures to respond to one or twolevers (omissions). Modafinil (30, 100 and 300 mg/kg) was administeredi.p. 30 minutes before each delayed alternation acquisition session, andcompared with a 23 month-old aged control group and a 2 month-old youngcontrol group. Eleven to 12 animals per group were used at the beginningof the drug testing period.

[0039] The results of these studies showed that the aged controls, incomparison with young controls, showed deficits in the acquisition andperformance of the delayed alternation task. This was indicated by poorresponse accuracy (impaired learning), slower reaction times and moreresponse omissions (impaired attention). Modafinil (30 mg/kg i.p.)significantly increased the number of correct responses (both weeks) andsignificantly decreased choice reaction times (second test week). Noclear effects were observed on simple reaction times, although atendency towards a decrease was apparent during the second test week.Modafinil (from 100 to 300 mg/kg i.p.) failed to improve the generalability of animals to perform the task. Indeed, some rats did notcomplete the minimal criteria of 20 trials during some sessions,therefore decreasing the number of animals retained for data analysis.Modafinil also tended to increase simple reaction times during thesecond test week and significantly increased the number of responseomissions, mainly during the one-lever presentations. No effects wereobserved at this dose on the number of correct responses.

[0040] As shown in FIG. 1A, aged rats receiving 30 mg/kg performed aswell as the young controls and significantly better than the agedcontrols in percent correct responses in the delayed alternation test,at least in sessions 2-9. As shown in FIG. 1B, however, this effect doesnot occur at 100 mg/kg modafinil, a level representing the lowerthreshold of wake-promoting doses.

[0041] All of the compositions and methods disclosed and claimed hereincan be made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the methods described herein without departing from theconcept, spirit and scope of the invention. More specifically, it willbe apparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

What is claimed is:
 1. A composition comprising a modafinil compound foradministration to a mammal, said composition comprising an amount of amodafinil compound effective to improve cognitive function in saidmammal.
 2. The composition of claim 1 , further defined as comprisingfrom about 1 mg to about 75 mg of said modafinil compound.
 3. Thecomposition of claim 1 , wherein said composition comprises from about 5to about 60 mg of said modafinil compound.
 4. The composition of claim 1, wherein said composition comprises from about 15 to about 50 mg ofsaid modafinil compound.
 5. The composition of claim 1 , wherein saidcomposition comprises from about 25 to about 40 mg of said modafinilcompound.
 6. The composition of claim 1 , wherein said compositioncomprises from about 30 to about 35 mg of said modafinil compound. 7.The method according to claim 1 , wherein said composition comprises anamount of modafinil compound effective to achieve a serum level in saidmammal of from about 0.05 to about 2 μg/ml modafinil when administeredto said mammal.
 8. The composition of claim 1 , wherein said modafinilcompound is modafinil.
 9. The composition of claim 1 , wherein saidmammal has or is susceptible to a loss of cognitive function due to age,trauma, stress, disease, or transient impairment due to chemicalimbalance or toxicity.
 10. The composition of claim 1 , wherein saidcomposition comprises an oral pharmaceutical preparation.
 11. Thecomposition of claim 1 , wherein said composition comprises a tablet fororal administration.
 12. The composition of 1, wherein said tabletcomprises lactose, corn starch, magnesium silicate, croscarmellosesodium, povidone, magnesium stearate, or talc.
 13. The composition ofclaim 1 , wherein said mammal is a human.
 14. The composition of claim 1, wherein said mammal is a human Alzheimer's disease, Age-RelatedCognitive Decline, or schizophrenia patient.
 15. A method of preparing acomposition for enhancement of cognitive function in a subject in needthereof comprising combining an amount of a modafinil compound effectiveto improve cognitive function in said mammal with a pharmaceuticallyacceptable carrier.
 16. The method of claim 15 , further defined ascomprising combining from about 1 to about 75 mg of modafinil with apharmaceutically acceptable carrier.
 17. The method of claim 15 ,further defined as comprising combining from about 5 to about 60 mg ofmodafinil with a pharmaceutically acceptable carrier.
 18. The method ofclaim 15 , further defined as comprising combining from about 15 toabout 50 mg of modafinil with a pharmaceutically acceptable carrier. 19.The method of claim 15 , further defined as comprising combining fromabout 25 to about 40 mg of modafinil with a pharmaceutically acceptablecarrier.
 20. The method of claim 15 , further defined as comprisingcombining from about 30 to about 35 mg of modafinil with apharmaceutically acceptable carrier.
 21. The method of claim 15 ,wherein said subject has or is susceptible to a loss of cognitivefunction due to age, trauma, stress, disease, or transient impairmentdue to chemical imbalance or toxicity.
 22. The method of claim 15 ,wherein said composition comprises an oral pharmaceutical preparation.23. The method of claim 15 , wherein said composition comprises a tabletfor oral administration.
 24. The method of claim 23 , wherein saidcomposition comprises lactose, corn starch, magnesium silicate,croscarmellose sodium, povidone, magnesium stearate, or talc in anycombination thereof.
 25. A method of improving a cognitive function inan animal or human subject comprising administering to said animal anamount of modafinil effective to improve said cognitive function. 26.The method of claim 25 , wherein said subject is a human.
 27. The methodof claim 25 , wherein said effective amount is substantially lower thanthe equivalent of 200 mg/day in a human adult.
 28. A method for treatingloss of cognition in a mammal susceptible to the development of orsuffering from cognition loss, which comprises administering to saidmammal amounts of a modafinil compound effective to stabilize or improvecognition in said mammal.
 29. The method of claim 28 , wherein saidamounts of modafinil compound being administered periodically in unitdoses that are substantially lower 200 mg/day dosages in said mammal.30. The method according to claim 28 , wherein said amounts of modafinilcompound are effective to achieve a serum level of from about 0.05 toabout 2 μg/ml modafinil in said subject.
 31. A method according to claim28 wherein said loss of cognition is associated with age, trauma,stress, disease, or transient impairment due to chemical imbalance ortoxicity.
 32. A method according to claim 28 wherein said loss ofcognition is associated with Age-Related Cognitive Decline, Alzheimer'sdisease, or schizophrenia.
 33. A method according to claim 28 whereinsaid unit doses provide daily doses of from about 1 mg to about 75 mgorally.
 34. A method according to claim 28 wherein said modafinilcompound is modafinil.
 35. A method according to claim 28 wherein saidmammal is a human subject.
 36. In a method for using a modafinilcompound in mammals as a medicine, the improvement which comprises:administering said modafinil compound in doses that are (a)substantially lower than the minimal optimal unit doses that areeffective to promote wakefulness in said mammal and (b) effective tostabilize or improve cognition in said mammal.
 37. An improvementaccording to claim 36 wherein said mammal is susceptible to thedevelopment of or suffering from a loss of cognitive function associatedwith age, trauma, stress, disease, or transient impairment due tochemical imbalance or toxicity.
 38. An improvement according to claim 36wherein said unit doses provide daily doses effective to achieve a serumlevel in said mammal of from about 0.05 to about 2 μg/ml.
 39. Animprovement according to claim 36 wherein said unit doses areadministered orally.
 40. An improvement according to claim 36 whereinsaid modafinil compound is modafinil.
 41. An improvement according toclaim 40 wherein said mammal is a human subject.
 42. A pharmaceuticalcomposition in unit dose form, for use in treating loss of cognitivefunction in a mammal susceptible to the development of or suffering froma loss of cognitive function, which comprises: an amount of a modafinilcompound such that one or more unit doses thereof are effective tostabilize or improve cognitive function in said mammal upon periodicadministration.
 43. The composition of claim 42 , wherein the unit dosesbeing administered periodically are substantially lower than 200 mg. 44.A pharmaceutical composition according to claim 42 wherein the amount ofthe modafinil compound contained in each unit dose provides a doseeffective to achieve a serum level of modafinil in said mammal of fromabout 0.05 to about 2 μg/ml.
 45. A pharmaceutical composition accordingto claim 42 wherein the amount of the modafinil compound contained ineach unit dose provides a dose effective to achieve a serum level ofmodafinil in said mammal of from about 0.05 to about 1.5 μg/ml.
 46. Apharmaceutical composition according to claim 42 wherein the amount ofthe modafinil compound contained in each unit dose provides a doseeffective to achieve a serum level of modafinil in said mammal of fromabout 0.1 to about 1.5 μg/ml.
 47. A pharmaceutical composition accordingto claim 42 wherein the amount of the modafinil compound contained ineach unit dose provides a dose effective to achieve a serum level ofmodafinil in said mammal of from about 0.5 to about 1.5 μg/ml.
 48. Apharmaceutical composition according to claim 42 wherein the amount ofthe modafinil compound contained in each unit dose provides a doseeffective to achieve a serum level of modafinil in said mammal of fromabout 0.5 to about 1 μg/ml.
 49. The pharmaceutical composition accordingto claim 42 wherein the composition comprises a tablet for oraladministration.
 50. The pharmaceutical composition according to claim 42, wherein said modafinil compound is modafinil.
 51. The pharmaceuticalcomposition according to claim 42 , wherein said mammal has or issusceptible to a loss of cognitive function due to age, trauma, stress,disease, or transient impairment due to chemical imbalance or toxicity.52. The pharmaceutical composition according to claim 48 , wherein saidtablet comprises lactose, corn starch, magnesium silicate,croscarmellose sodium, povidone, magnesium stearate, or talc.
 53. Thepharmaceutical composition according to claim 42 , wherein said mammalis a human.
 54. The pharmaceutical composition according to claim 42 ,wherein said mammal is a human Alzheimer's disease, Age-RelatedCognitive Decline, or schizophrenia patient.
 55. A therapeutic packagefor dispensing to, or for use in dispensing to, a mammal being treatedfor loss of cognition, comprising: (1) one or more unit doses, each suchunit dose containing an amount of a modafinil compound such that saidone or more unit doses thereof are effective to stabilize or improvecognition in said mammal upon periodic administration and the unit dosesbeing administered periodically are substantially lower than 200 mg/dayin said mammal, and (2) a finished pharmaceutical container therefor,said container containing (a) said unit dose or unit doses and (b)labeling directing the use of said package in the treatment of saidmammal.
 56. A therapeutic package according to claim 55 wherein the unitdose is adapted for oral administration.
 57. A method of treatingdementia in a human subject in need thereof, said method comprisingadministering to said subject a composition comprising modafinil in adaily dose that is effective to substantially improve said dementia andis lower than the minimal optimum daily dose that is effective topromote wakefulness in said human subject.
 58. The method according toclaim 56 , wherein said daily dose is an oral dosage of from about 1 toabout 75 mg.
 59. A method of treating dementia due to Alzheimer'sdisease in a human in need thereof, said method comprising administeringto said subject a composition comprising modafinil in a daily dose thatis effective to substantially improve said dementia and is lower than200 mg/day.
 60. The method according to claim 46 , wherein said dailydose is an oral daily dosage of from about 1 to about 75 mg.